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Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions

Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However,...

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Autores principales: Han, Kyung Ah, Kim, Jinhu, Kim, Hyeonho, Kim, Dongwook, Lim, Dongseok, Ko, Jaewon, Um, Ji Won
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863843/
https://www.ncbi.nlm.nih.gov/pubmed/31745231
http://dx.doi.org/10.1038/s41598-019-53519-1
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author Han, Kyung Ah
Kim, Jinhu
Kim, Hyeonho
Kim, Dongwook
Lim, Dongseok
Ko, Jaewon
Um, Ji Won
author_facet Han, Kyung Ah
Kim, Jinhu
Kim, Hyeonho
Kim, Dongwook
Lim, Dongseok
Ko, Jaewon
Um, Ji Won
author_sort Han, Kyung Ah
collection PubMed
description Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons.
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spelling pubmed-68638432019-11-20 Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions Han, Kyung Ah Kim, Jinhu Kim, Hyeonho Kim, Dongwook Lim, Dongseok Ko, Jaewon Um, Ji Won Sci Rep Article Members of the Slitrk (Slit- and Trk-like protein) family of synaptic cell-adhesion molecules control excitatory and inhibitory synapse development through isoform-dependent extracellular interactions with leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs). However, how Slitrks participate in activation of intracellular signaling pathways in postsynaptic neurons remains largely unknown. Here we report that, among the six members of the Slitrk family, only Slitrk2 directly interacts with the PDZ domain-containing excitatory scaffolds, PSD-95 and Shank3. The interaction of Slitrk2 with PDZ proteins is mediated by the cytoplasmic COOH-terminal PDZ domain-binding motif (Ile-Ser-Glu-Leu), which is not found in other Slitrks. Mapping analyses further revealed that a single PDZ domain of Shank3 is responsible for binding to Slitrk2. Slitrk2 forms in vivo complexes with membrane-associated guanylate kinase (MAGUK) family proteins in addition to PSD-95 and Shank3. Intriguingly, in addition to its role in synaptic targeting in cultured hippocampal neurons, the PDZ domain-binding motif of Slitrk2 is required for Slitrk2 promotion of excitatory synapse formation, transmission, and spine development in the CA1 hippocampal region. Collectively, our data suggest a new molecular mechanism for conferring isoform-specific regulatory actions of the Slitrk family in orchestrating intracellular signal transduction pathways in postsynaptic neurons. Nature Publishing Group UK 2019-11-19 /pmc/articles/PMC6863843/ /pubmed/31745231 http://dx.doi.org/10.1038/s41598-019-53519-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Han, Kyung Ah
Kim, Jinhu
Kim, Hyeonho
Kim, Dongwook
Lim, Dongseok
Ko, Jaewon
Um, Ji Won
Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title_full Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title_fullStr Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title_full_unstemmed Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title_short Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions
title_sort slitrk2 controls excitatory synapse development via pdz-mediated protein interactions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863843/
https://www.ncbi.nlm.nih.gov/pubmed/31745231
http://dx.doi.org/10.1038/s41598-019-53519-1
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